Fructokinase (ketohexokinase, KHK) is a key enzyme in fructose metabolism, and phosphorylates fructose to fructose-1-phosphate. In turn, fructose 1-phosphate is metabolized by aldolase B and triokinase to dihydroxyacetone phosphate and glyceraldehyde 3-phosphate, which leads eventually to glycolysis and the generation of triglycerides. Two major isoforms of fructokinase exist, consisting of fructokinase C (KHK-C), which is the principal fructokinase isoform present in small intestine, liver and kidney, and fructokinase A (KHK-A), which is expressed in most tissues, and especially in skeletal muscle.
Recent studies suggest that excessive ingestion of fructose, primarily in the form of added sugars, such as high fructose corn syrup (HFCS) and sucrose, may have a role in the epidemic of obesity and diabetes.(1-2) The administration of high concentrations of fructose to animals(3) and to humane(2, 4) can induce features of metabolic syndrome, including insulin resistance, hypertriglyceridemia, low HDL cholesterol, fatty liver, and elevated blood pressure. These features are not seen in subjects administered equivalent amounts of glucose or starch.(2) These types of studies, as well as experiments in animal models, have clearly demonstrated that the effects of fructose to induce metabolic syndrome are independent of excessive energy intake.(5) 
Further, all animals like sugar (sucrose), as the stimulation of sweet taste causes a feeling of pleasantness as a consequence of stimulating dopamine in the brain.1-2 In addition to sucrose, other sweet substances, such as glucose, fructose, and artificial sugars (sucralose) can also stimulate dopamine responses. However, it has been shown that the repeated ingestion of sugar in mice can lead to a craving or addiction syndrome. These animals develop features similar to that observed with drug addiction, and will show signs of anxiety or withdrawal following elimination of sugar from the diet or the administration of naloxone.3-4 The mechanism appears to relate to a reduction in dopamine receptors (especially D2 receptors) in the nucleus accumbens from chronic dopamine stimulation, leading to a loss of control mechanisms in the frontal and prefrontal cortex.5 The importance of this pathway is being increasingly recognized as a mechanism that results in lack of normal control, and may have a role in the pathogenesis of obesity, attention deficit hyperactivity disorder, and even aggressive behavior and dementia.2, 6-10 Thus, identifying a way to prevent the craving for sugar might be of great benefit in reducing the frequency of these conditions.
Fructose has also been shown to induce leptin resistance and to encourage increased food intake in rats.(9) Others have also suggested fructose may not quench satiety, either based on effects on systemic release of insulin and ghrelin(10) or as a consequence of central effects.(11) Thus, fructose ingestion may cause weight gain.
The mechanism by which fructose induces metabolic syndrome is not completely known, but appears to be mediated by the ability of fructose to raise uric acid levels, and induce endothelial dysfunction and oxidative stress.(3, 6) Since the generation of uric acid occurs during the phosphorylation of fructose by fructokinase, we have postulated that fructokinase is responsible for the development of metabolic syndrome in response to fructose.(1, 7) 
To date, studies inhibiting fructokinase are limited. We reported that the metabolism of fructose by fructokinase in kidney proximal tubular cells could produce a prooxidative response with the generation of uric acid and inflammatory mediators.(8) Knocking down fructokinase with a specific siRNA was able to block this proinflammatory response.(8) 
While the above studies suggest fructokinase may have important roles in metabolic syndrome, we have identified several novel roles for fructokinase and its isoforms which constitute the basis for this patent application.